12-21438095-G-C

Variant names:

• chr12-21438095-G-C
• rs113058309
• NM_024854.5:c.84+281G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001350912.2(PYROXD1):​c.-573G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 429,496 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (37 hom., cov: 33)
  • Exomes 𝑓: 0.020 (85 hom.)
• Consequence: PYROXD1 NM_001350912.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

Genes affected

PYROXD1 (HGNC:26162): (pyridine nucleotide-disulphide oxidoreductase domain 1) This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

PYROXD1 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-21438095-G-C is Benign according to our data. Variant chr12-21438095-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1183822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0201 (3055/152288) while in subpopulation AFR AF = 0.0247 (1027/41560). AF 95% confidence interval is 0.0235. There are 37 homozygotes in GnomAd4. There are 1498 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350912.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	NM_024854.5	MANE Select	c.84+281G>C		intron	N/A	NP_079130.2	Q8WU10-1
	PYROXD1	NM_001350912.2		c.-573G>C		5_prime_UTR	Exon 1 of 12	NP_001337841.1	Q8WU10-2
	PYROXD1	NM_001350913.2		c.-620+281G>C		intron	N/A	NP_001337842.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.84+281G>C		intron	N/A	ENSP00000240651.9	Q8WU10-1
	PYROXD1	ENST00000544970.5	TSL:1	n.84+281G>C		intron	N/A	ENSP00000439106.1	B4DEW4
	PYROXD1	ENST00000538582.5	TSL:2	c.-573G>C		5_prime_UTR	Exon 1 of 12	ENSP00000438505.1	Q8WU10-2

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3038 AN: 152170 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0200 AC: 5551 AN: 277208 Hom.: 85 Cov.: 0 AF XY: 0.0200 AC XY: 2867 AN XY: 143252

African (AFR) AF: 0.0244 AC: 172 AN: 7038

American (AMR) AF: 0.0137 AC: 130 AN: 9474

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 132 AN: 9550

East Asian (EAS) AF: 0.00 AC: 0 AN: 20670

South Asian (SAS) AF: 0.0126 AC: 209 AN: 16530

European-Finnish (FIN) AF: 0.0187 AC: 383 AN: 20502

Middle Eastern (MID) AF: 0.0537 AC: 73 AN: 1360

European-Non Finnish (NFE) AF: 0.0233 AC: 4066 AN: 174454

Other (OTH) AF: 0.0219 AC: 386 AN: 17630

GnomAD4 genome AF: 0.0201 AC: 3055 AN: 152288 Hom.: 37 Cov.: 33 AF XY: 0.0201 AC XY: 1498 AN XY: 74454

African (AFR) AF: 0.0247 AC: 1027 AN: 41560

American (AMR) AF: 0.0141 AC: 216 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4814

European-Finnish (FIN) AF: 0.0201 AC: 213 AN: 10616

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0208 AC: 1417 AN: 68024

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0196 Hom.: 5

Bravo AF: 0.0203

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.60
PhyloP100		2.2
PromoterAI		0.0038	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113058309; hg19: chr12-21591029;